A growing body of evidence supports a role for antibodies against neurotropic viruses, often through only partially characterized non-lytic mechanisms. The present application is aimed at the elucidation of antibodies mechanisms of action in herpes simplex virus (HSV) infection and the means by which human recombinant monoclonal antibodies could be exploited prophylactically and therapeutically. Previous work as well as studies conducted during the current funding have demonstrated that antibodies of exceptional efficacy are generated in the course of the natural human immune response to HSV and other viruses, and can be isolated by recombinant techniques. During the current funding period recombinant antibody libraries were established as were several new human monoclonal antibodies; a novel vector for the rapid expression whole antibodies in eukaryotic cells was also established and used for the conversion recombinant Fabs into whole antibodies and for the construction of recombinant antibody fusions with interferon and IL-12. Aspects of antibody synergism and the neurobiology of antibodies' action against HSV were also investigated. The investigator now propose to investigate the biological bases for the antibodies actions in protection and pathogenesis in neurotropic virus infections using recombinant antibodies engineered to circumvent IgG binding by HSV Fc receptor, a putative mechanism of humoral immune evasion by HSV, and genetically engineered antibodies devoid of the ability to recruit host effector mechanisms. They also propose to explore the therapeutic potential of the mentioned immunocytokines generated by fusing recombinant antibodies with cytokines such as interferon and IL-2 which have been shown to possess anti-HSV activities. It is expected that the results of these studies will contribute to the understanding of the mechanisms behind the protective activities of antibodies against HSV and other neurotropic viruses and to the development of novel and effective therapeutic strategies to reduce morbidity and mortality by these agents. Examples of possible practical applications of the proposed research include prophylaxis of HSV infections in the newborn, and more efficacious management of drug-resistant strains of HSV in immunodepressed patients.